The role of hippocampal NMDA receptors in long-term emotional responses following muscarinic receptor activation

Extensive evidence indicates the influence of the cholinergic system on emotional processing. Previous findings provided new insights into the underlying mechanisms of long-term anxiety, showing that rats injected with a single systemic dose of pilocarpine--a muscarinic receptor (mAChR) agonist--displayed persistent anxiogenic-like responses when evaluated in different behavioral tests and time-points (24 h up to 3 months later). Herein, we investigated whether the pilocarpine-induced long-term anxiogenesis modulates the HPA axis function and the putative involvement of NMDA receptors (NMDARs) following mAChRs activation. Accordingly, adult male Wistar rats presented anxiogenic-like behavior in the elevated plus-maze (EPM) after 24 h or 1 month of pilocarpine injection (150 mg/kg, i.p.). In these animals, mAChR activation disrupted HPA axis function inducing a long-term increase of corticosterone release associated with a reduced expression of hippocampal GRs, as well as consistently decreased NMDAR subunits expression. Furthermore, in another group of rats injected with memantine--an NMDARs antagonist (4 mg/kg, i.p.)--prior to pilocarpine, we found inhibition of anxiogenic-like behaviors in the EPM but no further alterations in the pilocarpine-induced NMDARs downregulation. Our data provide evidence that behavioral anxiogenesis induced by mAChR activation effectively yields short- and long-term alterations in hippocampal NMDARs expression associated with impairment of hippocampal inhibitory regulation of HPA axis activity. This is a novel mechanism associated with anxiety-like responses in rats, which comprise a putative target to future translational studies

FITOQUÍMICA E ATIVIDADE FARMACOLÓGICA PRELIMINAR DO EXTRATO AQUOSO DE Tynanthus micranthus Corr. Méllo ex K. Schum: UM EXEMPLO DA CAPACIDADE PREDITIVA E DOS CUSTOS NO DESENVOLVIMENTO DE NOVOS PRODUTOS FARMACÊUTICOS

Os produtos naturais têm servido de inspiração para o desenvolvimento de vários produtos pela indústria farmacêutica local e mundial. O objetivo do presente trabalho foi avaliar a atividade farmacológica preliminar do extrato aquoso das folhas secas de Tynanthus micranthus, usando o teste hipocrático em camundongos, como uma ferramenta para direcionar estudos farmacológicos futuros, bem como avaliar os custos envolvidos na execução deste estudo. AT. micranthus Corr. Méllo ex K. Schum, conhecida popularmente como cipó-cravo, é facilmente encontrada na região Noroeste do Estado do Paraná, Brasil, sendo utilizada pela população como calmante e analgésica. No entanto, existem poucos trabalhos científicos com esta espécie vegetal. O cálculo do custo contábil foi realizado para simular o valor gasto por uma empresa privada na realização destas atividades de Pesquisa e Desenvolvimento. Nossos resultados mostram que além do baixo custo, o teste hipocrático proporciona resultados importantes para a decisão da via de administração, toxicidade aguda, efeitos com altas doses e por diferentes vias, além de fornecer informações sobre a latência para os efeitos observados. Com essas informações e uma análise fitoquímica mais aprofundada, isolando e identificando os compostos majoritários, é possível avaliar na literatura a relação composto x atividade farmacológica direcionando de forma mais assertiva as pesquisas a serem realizadas. De maneira geral, apresentamos dados inéditos da espécie estudada (T. micranthus), mostrando uma estratégia de triagem farmacológica simples e de baixo custo para a pesquisa de plantas medicinais nativas que apresentem informações restritas na literatura e que possam servir para o desenvolvimento de novos produtos farmacêuticos

Alpha cluster structure in 16O.

The alpha cluster phenomenon in the light nuclei structure has been the subject of a longtime\ud investigation since the proposal of the Ikeda diagrams, however the mechanism of the cluster\ud formation is still not completely understood. In fact, if the clusters have a fairly rigid crystal-like or a\ud gas-like structure remains an open question. The interpretation of the Hoyle state as an α\ud condensate brought a renewed interest to this subject, in particular to resonances analogous to the\ud Hoyle state. In this context the study of the experimental evolution of the α-cluster phenomenon\ud through (6Li,d) transfer reactions has been performed in São Paulo. Particularly important are the\ud regions around the nα thresholds where the α-cluster structure states are predicted. The resonant\ud states around the 4α threshold in the nucleus 16O are the focus of the present contribution. The\ud 12C(6Li,d)16O reaction was measured at a bombarding energy of 25.5 MeV employing the São Paulo\ud Pelletron-Enge-Spectrograph facility and the nuclear emulsion detection technique. Resonant states\ud above the α threshold were measured and an energy resolution of 15-30 keV allows to define states\ud previously unresolved. The angular distributions of the absolute cross sections were determined in a\ud range of 4-40 degree in the center of mass system and up to 17 MeV excitation energy. The upper\ud limit for the resonance widths in the crucial region of the 4α threshold was obtained. These values\ud revealed to be at least a factor three smaller than the ones previously reported in the literature,\ud indicating that the α cluster structure information on this region should be revised

Structure and Behavior of Human α-Thrombin upon Ligand Recognition: Thermodynamic and Molecular Dynamics Studies

Thrombin is a serine proteinase that plays a fundamental role in coagulation. In this study, we address the effects of ligand site recognition by alpha-thrombin on conformation and energetics in solution. Active site occupation induces large changes in secondary structure content in thrombin as shown by circular dichroism. Thrombin-D-Phe-Pro-Arg-chloromethyl ketone (PPACK) exhibits enhanced equilibrium and kinetic stability compared to free thrombin, whose difference is rooted in the unfolding step. Small-angle X-ray scattering (SAXS) measurements in solution reveal an overall similarity in the molecular envelope of thrombin and thrombin-PPACK, which differs from the crystal structure of thrombin. Molecular dynamics simulations performed with thrombin lead to different conformations than the one observed in the crystal structure. These data shed light on the diversity of thrombin conformers not previously observed in crystal structures with distinguished catalytic and conformational behaviors, which might have direct implications on novel strategies to design direct thrombin inhibitors

Evaluation of antinociceptive effect of Petiveria alliacea (guiné) in animals

Petiveria alliacea (Phytolaccaceae) is a bush widely distributed in South America including Brazil, where it is popularly known as "guiné", pipi", "tipi" or "erva-de-tipi". Brazilian folk medicine attributes to the hot water infusion of its roots or leaves the following pharmacologicalproperties: antipyretic, antispasmodic, abortifacient, antirrheumatic, diuretic, analgesic and sedative. The present study has evaluated the alleged effects of P. alliacea on central nervous system (CNS), particularly, the sedative and analgesic properties of root crude aqueous extract of this plant in mice and rats. This extract showed an antinociceptive effect in acetic acid - acetylcholine - and hypertonic saline - induced abdominal constrictions, but not in hot-plate and tail flick tests P. alliacea did not produce any CNS depressor effect. Thus its antinociceptive action in animals can be responsible by its poplar use as an analgesic

Involvement of GABAergic pathway in the sedative activity of apigenin, the main flavonoid from Passiflora quadrangularis pericarp

AbstractIn the current study we showed that oral administration of an aqueous extract of Passiflora quadrangularis L., Passifloraceae, pericarp results in a significant prolongation of the sleep duration in mice evaluated in the ethyl ether-induced hypnosis test which indicates sedative effects. Apigenin, the main flavonoid of the extract, induced a similar sedative response when applied alone, at a dose equivalent to that found in the extract, suggesting that apigenin is mediating the sedative effects of P. quadrangularis extract. In addition, the sedative effect of apigenin was blocked by pretreatment with the benzodiazepine antagonist flumazenil (1mg/kg), suggesting an interaction of apigenin with gamma-aminobutyric acid type A (GABAA) receptors. However, apigenin at concentrations 0.1–50μM failed to enhance GABA-induced currents through GABAA receptors (α1β2γ2S) expressed in Xenopus oocytes. Nevertheless, based on our results, we suggest that the in vivo sedative effect of the P. quadrangularis extract and its main flavonoid apigenin maybe be due to an enhancement of the GABAergic system